While there have been vast improvements in vascular intervention to combat vascular occlusive diseases, restenosis (occlusion of the vessel) following the intervention remains a major clinical problem. The long-term goal of this proposal is to elucidate key factors that control changes in VSMC behavior associated with vascular occlusive disease and to design novel engineered biomaterials that can probe and control this behavior. While there have been extensive studies examining the biochemical effects of changes in the ECM, comparatively little attention has been focused on the effects of the biomechanical properties of the ECM on VSMC phenotype. Our preliminary data show that both (i) VSMC signaling induced by platelet-derived growth factor (PDGF) and (ii) VSMC directional migration are modulated significantly by substrate stiffness. We further find that substrate stiffness influences ECM deposition (collagen type I and III) and the production and secretion of matrix metalloproteinases (MMP) -2 and -9 that are known to degrade the matrix. Based on these observations, our central hypothesis is that the local mechanical environment has an essential role in vascular homeostasis and broad modulatory effects on the structural composition of ECM. We further hypothesize that initial injury promotes a VSMC phenotypic switch that subsequently contributes via positive feedback to the development of vascular occlusive diseases. To test these hypotheses, we will use a multi-scale approach to explore the effect of biomechanical environment on the molecular level, on cells, tissues, and tissue-engineered biomimetic model systems. We will use VSMCs and also native vessels from normal and atherosclerotic animals (Watanabe Hereditable Hyperlipidemic rabbit) to achieve clinical relevance. Specific Aim 1: Investigate the interrelationship of mechanical properties such as compliance and ECM and develop physiologically-relevant bioengineered model substrata. Specific Aim 2: Determine the effects of mechanical environment on VSMC phenotypic modulation on bioengineered substrata mimicking physiological and pathological conditions of blood vessels. Specific Aim 3: Characterize the effects of mechanical environment and biochemical changes on vessel behavior by tissue culture under in vivo-like conditions. Validation of our bioengineered substrata results in tissue cultures will yield valuable data, establishing a mechanistic foundation for elucidating the role of biomechanics on ECM remodeling and VSMC phenotype. The successful completion of these aims will lead to new strategies to control VSMC phenotype related to vascular occlusive disease by targeting regulation of ECM biomechanical properties of the vessel wall. PUBLIC HEALTH RELEVANCE: This proposal seeks to understand the mechanisms that control the switching behavior of a major cell type in blood vessels that play a key role in the progression of atherosclerosis the leading cause of death in the Western world. Through researching these specific mechanisms, we have the potential to uncover novel therapeutic strategies to treat cardiovascular disease.